EP0386688A1 - Verfahren zur Herstellung von Hydrogelen und Xerogelen - Google Patents
Verfahren zur Herstellung von Hydrogelen und Xerogelen Download PDFInfo
- Publication number
- EP0386688A1 EP0386688A1 EP90104245A EP90104245A EP0386688A1 EP 0386688 A1 EP0386688 A1 EP 0386688A1 EP 90104245 A EP90104245 A EP 90104245A EP 90104245 A EP90104245 A EP 90104245A EP 0386688 A1 EP0386688 A1 EP 0386688A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- preparations
- pentoxifylline
- xerogel
- hydrogel
- preparing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
Definitions
- This invention relates to a method for preparing hydrogel preparations and xerogel preparations containing a medicinal component such as pentoxifylline, a cerebral microcirculation-improving agent, or propentofylline, a cerebral nerve cell-protecting and function-improving agent.
- a medicinal component such as pentoxifylline, a cerebral microcirculation-improving agent, or propentofylline, a cerebral nerve cell-protecting and function-improving agent.
- hydrogels have widely been investigated as a medical material because of their high affinity to organic tissues.
- agar, carragenan, collagen, gelatin, alginic acid, polyvinyl alcohol or the like are well known as medicinal component-containing hydrogel preparations.
- hydrogel preparations have an advantage in that they give little damage to organic tissues, they are disadvantageous in that they have high water content which unfavorably affect mechanical strength and greatly limit their application. Consequently, most of the hydrogel preparations are directed to application to skin, and the presently available preparations are very rarely directed to oral administration, implanting or rectal administration. Extensive studies have recently been made for longer duration of the blood level and efficacy of drugs using a sustained-releasing preparation and attention has been called thereto. However, there are almost no hydrogel preparations found to be successiveful in achieving sustained release.
- the present invention relates to a novel method for preparing hydrogel preparations which comprises suspending an acrylic copolymer in an aqueous solution, suspension or emulsion of a medicinal component such as pentoxifylline or propentofylline in advance dissolved, suspended or emulsified, then adding thereto an aqueous alkaline solution and uniformly stirring the mixture.
- a novel method for preparing hydrogel preparations which comprises suspending an acrylic copolymer in an aqueous solution, suspension or emulsion of a medicinal component such as pentoxifylline or propentofylline in advance dissolved, suspended or emulsified, then adding thereto an aqueous alkaline solution and uniformly stirring the mixture.
- the invention is concerned with a novel method for preparing xerogel preparations which comprises freezing the hydrogel preparation thus obtained at a temperature of -10°C below and drying in vacuo the frozen mass.
- the acrylic copolymer used in the method of the invention is desirably a methacrylic acid-methyl methacrylate copolymer.
- aqueous alkaline solution an aqueous solution of sodium hydroxide, potassium hydroxide, calcium hydroxide, ethylenediamine, triethanolamine or the like.
- sodium hydroxide is especially desirable.
- the hydrogels have preferably a pH value of smaller than weakly alkaline.
- the range between 3.0 and 5.75 mmol per gram of Eudragit L, between 3.0 and 3.5 mmol per gram of Eudragit S, or between 4.0 and 7.5 mmol per gram of Eudispert hv, mv or nv is desirable. If a less or no amount is incorporated, there will be produced no hydrogel preparation at all. If a more amount is incorporated, the hydrogel preparation will become weakly or strongly alkaline and not be applicable to living body.
- a variety of medicinal components can be used, for example, non-steroidal antiinflammatory and analgesic agents, anticancer agents, hypotensives, antiarrhythmic agents, antiallergic agents, antihistaminic agents, psychotropic agents, diuretics, bronchodillators and other systemic medicinal agents and local anesthetic agents such as procaine hydrochloride and lidocaine hydrochloride.
- Particularly preferable medicinal components are pentoxifylline, propentofylline, furosemide, piretanide, ketoprofen, ibuprofen, naproxen, flurbiprofen, diclofenac sodium, loxoprofen sodium, fenbufen, alclofenac, indomethacin, piroxicam, mefenamic acid, propranolol, procaine hydrochloride, lidocaine hydroxide, theophylline, peptides, for example buserelin.
- a medicinal component for example, pentoxifylline
- an acrylic copolymer such as a methacrylic acid-methyl methacrylate copolymer (for example, Eudispert hv) in a range of 1-20 % (w/w) of the total weight.
- the mixture is mechanically stirred and allowed to soak and swell for 10-15 min.
- To the resulting mixture is added with stirring 4.0-7.5 mmol of an aqueous alkaline solution (for example, an aqueous solution of sodium hydroxide). Stirring is terminated immediately when coagulated.
- an aqueous alkaline solution for example, an aqueous solution of sodium hydroxide
- the product is an opaque coagulated mass at this stage but becomes a transparent uniform hydrogel preparation as gelation progresses.
- hydrogel preparations in various forms including solution, gel, jelly and sponge can be prepared. If the mixture of a medical component and an acrylic copolymer are filled in an appropriate forming vessel before coagulation but after adding an aqueous alkaline solution with stirring, there can be prepared a hydrogel preparations with the desired form maintained, for example the form of a spindle.
- a hydrogel preparations with the desired form maintained, for example the form of a spindle.
- the hydrogel preparation obtained above is degassed by an appropriate means (for example, centrifugation, ultrasonication), then filled in an appropriate forming vessel (for example, a plastic mold for the formation of suppositories or a polypropylene syringe cut to an appropriate length) and frozen by cooling at a temperature of -10°C or below (desirably around -70 - -80°C).
- an appropriate forming vessel for example, a plastic mold for the formation of suppositories or a polypropylene syringe cut to an appropriate length
- the hydrogel thus forzen is rapidly transferred into a freezing flask which has been cooled to around the above-mentioned temperature and immediately subjected to vacuum drying for a predetermined period of time. Then, there can be prepared a xerogel preparation with the desired form maintaned.
- the coolant there may be employed dry ice-acetone, dry ice-methanol, liquid nitrogen or the like as needed. If formed while maintaining a geometrical form such as spindle shape, cylinder or sphere, it is necessary to set the vacuum drying time in such a manner that the water content is not completely eliminated (for example, 3-5 % of the water content remains uneliminated). Thus, it is a distinct characteristic of the invention to allow a very small amount of water remained to act as binder between the polymer chains so that the form of the xerogel is kept unchanged.
- the vacuum drying time is set at about 6-8 hours when a freeze-drying vessel used on a laboratory scale is employed, though it is variable depending upon grade of the instrument used.
- a powdery xerogel after complete drying is to be produced, an intact hydrogel is subjected to the above-described procedures in a freezing flask to attain freeze drying to a constant weight without advance transfer of the hydrogel to a forming vessel.
- the xerogels formed into spindles or cylinders can be employed mainly, as a preparation for rectal administration, and the powdery xerogels can be employed as a preparation for oral administration or implanting after graded and filled into capsules, or mechanically compressed and formed by means, for example, of a tabletting machine to prepare a matrix preparation.
- the xerogel preparations designed for rectal administration can easily be applied to patients having difficulties in oral administration such as children and aged persons, and have the merit of letting the medicinal component (for example, pentoxifylline and propentofylline), which might be reduced in its efficacy by the first passing through liver after oral administration, pass from rectum directly into circulation.
- the medicinal component for example, pentoxifylline and propentofylline
- reaction mixture is filled in plastic molds each contaning 2 g of the mixture and allowed to stand until gelation is completed. There is produced a clear, homogeneous hydrogel preparation in spindles containing 2.5 % pentoxifylline designated for rectal administration.
- ketoprofen To 0.25 g of ketoprofen there are added 4.75 g of purified water and 1.5 g of Eudispert hv. The mixture is stirred for 10 min. and then allowed to stand for 10 min. at room temperature. To the resulting mass there are added with stirring 3.5 ml of a 3N aqueous solution of sodium hydroxide. The stirring is terminated when coagulation occurs. The reaction mixture is allowed to stand until gelation is completed. There is produced a clear, homogeneous hydrogel preparation containing 2.5 % ketoprofen.
- ketoprofen To 50 g of ketoprofen there are added 400 ml of purified water and 200 g of Eudragit S. The mixture is stirred for 10 min. followed by addition with stirring of 150 ml of 4N sodium hydroxide solution. The same procedures as in Example 12 are followed. There are obtained matrix tablets each having a weight of approximately 260 mg (each containing 50 mg of ketoprofen) for oral administration.
- buserelin acetate there are added 475 ml of purified water and 150 g of Eudispert mv. The mixture is stirred for 15 min. followed by addition with stirring of 350 ml of a 3N aqueous solution of sodium hydroxide. Hydrogel thus obtained is dried in vacuo to a constant weight. Xerogel thus produced is pulverized by means of a pulverizer, granules having particle sizes of 250-500 ⁇ m are collected and then tabletted to obtain a matrix preparation having a tablet weight of approximately 35 mg (100 ⁇ g of buserelin acetate per tablet) for implanting.
- 2,(- ⁇ -) represent the plasma pentoxifylline level in ⁇ g/ml after administration of an Eudispert hv-hydrogel preparation (4,5 g of a 5,56 % aqueous solution of pentoxifylline, 3,0 g of Eudispert hv, 2,5 ml of 6N NaOH) and - ⁇ - represents the plasma pentoxifylline level after the administration of the control suppository respectively.
- hydrogel or xerogel preparations and a control suppository in spindle shape each containing 50 mg of pnetoxifylline designed for rectal administration were subjected to a drug release test by the Muranishi method.
- a release test apparatus for suppository of Muranishi type (Model TMS-1U3; manufactured by Toyama Sangyo) was used.
- a hydrogel or a xerogel suppository prepared according to the method of invention in analogy to Examples 1 to 14 or Witepsol S-55 suppository (control suppository) each containing 50 mg of pentoxifylline was carefully placed on a screen at the bottom of a cylindrical cell which had been set in a depth of 2 mm from the liquid surface of the release phase (0.2 M KH2PO4 - 0.2 N NaOH buffer, pH 7.4, 500 ml, 37°C), and immediately thereafter the test was initiated.
- the release phase and the cell were stirred during the test at a rate of 100 rpm and 10 rpm, respectively.
- the curves in Fig. 3 respectively represent a pentoxifylline-releasing curve for the preparations of Table 2 Table 2 Fig. 3
- Example NaOH Concent. Amount Pentoxifylline Eudispert Amount Preparation type Concent. Amount - ⁇ - 1 3N 3.5 ml 5 % 5.0 g 1.5 g of Eudispert hv Hydrogel preparation - ⁇ - 9 3N 3.5 ml 5 % 5.0 g 1.5 g of Eudispert hv Xerogel preparation - ⁇ - 10 3N 2.5 ml 3.85 % g g 1.0 g of Eudispert hv Xerogel preparation - ⁇ - - 3N 3.5 ml 3.85 % 6.5 g 1.0 g of Eudispert hv Xerogel preparation - ⁇ - - 3N 3.5 ml 3.85 % 6.5 g 1.0 g of Eudispert hv Xerogel preparation - ⁇ - Control
- the curves in Fig. 4 represent a plasma concentration-time curve of pentoxifylline respectively for the preparations of Table 3 Table 3 Fig. 4
- Amount Pentoxifylline Eudispert Amount Preparation type Concent.
- the drug in a release experiment using an apparatus which allows a solvent to contact with a constant area (for example, the rotating disc method), the drug exhibited a zero order-releasing behavior (see Fig. 1). It is also demonstrated that release of pentoxifylline from the cylinder-form xerogel is more controllable than that from the Witepsol suppository or the hydrogel and that the xerogel is useful as rectal gel preparation of controlled release type (see Fig. 3).
- the plasma drug concentration-time curve produced when the present hydrogel or xerogel preparation is rectally given to rabbits indicates a favorable pattern of sustained releasing which represents 1.4-fold increase of the relative bioavailability as compared with the control suppository (see Fig. 2 and Fig.
- the present hydrogel preparations are useful for topical or rectal administration as unprecedented and entirely new sustained-release, longlasting preparation of depot-type, and furthermore, expected for a wide range of applications including those for senile dementia patients and pediatric patients.
- a variety of medicinal components including those easily inactivated by the first passing through liver can be imbedded in the present hydrogel preparations, which makes the invention highly vauable.
- the xerogel preparation which has a firmer structure as compared with the hydrogel preparation is more easily handled for administration.
- the present xerogel preparations are useful for rectal or oral administration as unprecedented and entirely new type of sustained-release preparation and expected for a wide range of applications including those for senile dementia patients and pediatric patients.
- a variety of medicinal components including those easily inactivated by the first passing through liver can be imbedded in the present xerogel preparations, which makes the invention highly valuable.
- xerogel preparations of various forms can be produced by controlling the forming operation, nature of the forming apparatus and time for freeze drying, which enable a wide range of applications in the living body.
- the preparation method of the present invention is very useful in providing preparations highly valuable in pharmaceutical industry.
- Fig. 1 and Fig. 3 represent a pentoxifylline-releasing curve respectively for the hydrogel preparation (by the rotating disc method) and the xerogel preparation (by the Muranishi method).
- Fig. 2 and Fig. 4 respectively represent a plasma concentration curve of pentoxifylline for the hydrogel preparation and the xerogel preparation.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Processes Of Treating Macromolecular Substances (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Colloid Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Compositions Of Macromolecular Compounds (AREA)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP53779/89 | 1989-03-08 | ||
JP5377989 | 1989-03-08 | ||
JP1234759A JPH0347134A (ja) | 1989-03-08 | 1989-09-12 | ヒドロゲル製剤およびキセロゲル製剤の製造法 |
JP234759/89 | 1989-09-12 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0386688A1 true EP0386688A1 (de) | 1990-09-12 |
EP0386688B1 EP0386688B1 (de) | 1993-04-21 |
Family
ID=26394489
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP90104245A Expired - Lifetime EP0386688B1 (de) | 1989-03-08 | 1990-03-06 | Verfahren zur Herstellung von Hydrogelen und Xerogelen |
Country Status (13)
Country | Link |
---|---|
EP (1) | EP0386688B1 (de) |
JP (1) | JPH0347134A (de) |
KR (1) | KR900013939A (de) |
CN (1) | CN1048659A (de) |
AT (1) | ATE88356T1 (de) |
AU (1) | AU632794B2 (de) |
CA (1) | CA2011682A1 (de) |
DE (1) | DE69001372T2 (de) |
DK (1) | DK0386688T3 (de) |
ES (1) | ES2055192T3 (de) |
IE (1) | IE900812L (de) |
NZ (1) | NZ232797A (de) |
PT (1) | PT93358A (de) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GR1002351B (el) * | 1994-01-14 | 1996-05-29 | Bristol-Myers Squibb Company | Αντιφλεγμονωδεις συνθεσεις που περιεχουν πιροξικαμ (piroxicam). |
WO1998005360A2 (de) * | 1996-08-01 | 1998-02-12 | Basf Aktiengesellschaft | Verwendung von (meth)acrylsäure-copolymeren zur erhöhung der permeabilität der schleimhaut |
US6312724B1 (en) | 1997-04-04 | 2001-11-06 | Isa Odidi | Sustained release pharmaceutical matrix tablet of pharmaceutically acceptable salts of diclofenac and process for preparation thereof |
WO2014116770A1 (en) * | 2013-01-23 | 2014-07-31 | Arx, Llc | Production of unit dose constructs |
EP2724716B1 (de) * | 2011-06-23 | 2017-11-22 | Prokrea Bcn, S.L. | Phosphodiestherase-inhibitoren zur transvaginaler verwendung in der behandlung der unfruchtbarkeit |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102145022B1 (ko) * | 2018-08-14 | 2020-08-14 | 동아제약 주식회사 | 이부프로펜의 현탁액 조성물 및 투여 제형 |
CN113143845A (zh) * | 2020-10-13 | 2021-07-23 | 西北师范大学 | 一种丙烯酰胺-盐酸普奈洛尔水凝胶及其制备方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2355510A1 (fr) * | 1976-06-21 | 1978-01-20 | Toko Yakuhin Kogyo Kk | Procede de production de compositions pharmaceutiques renfermant un melange de solution aqueuse de polymere carboxyvinylique avec un compose basique |
US4525348A (en) * | 1983-12-19 | 1985-06-25 | Yoshitomi Pharmaceutical Industries, Ltd. | Pranoprofen gelled ointment |
-
1989
- 1989-09-12 JP JP1234759A patent/JPH0347134A/ja active Pending
-
1990
- 1990-03-06 DK DK90104245.7T patent/DK0386688T3/da active
- 1990-03-06 EP EP90104245A patent/EP0386688B1/de not_active Expired - Lifetime
- 1990-03-06 DE DE9090104245T patent/DE69001372T2/de not_active Expired - Fee Related
- 1990-03-06 AT AT90104245T patent/ATE88356T1/de not_active IP Right Cessation
- 1990-03-06 ES ES90104245T patent/ES2055192T3/es not_active Expired - Lifetime
- 1990-03-06 NZ NZ232797A patent/NZ232797A/en unknown
- 1990-03-07 AU AU50748/90A patent/AU632794B2/en not_active Ceased
- 1990-03-07 KR KR1019900002968A patent/KR900013939A/ko not_active Application Discontinuation
- 1990-03-07 CA CA002011682A patent/CA2011682A1/en not_active Abandoned
- 1990-03-07 IE IE900812A patent/IE900812L/xx unknown
- 1990-03-07 PT PT93358A patent/PT93358A/pt not_active Application Discontinuation
- 1990-03-08 CN CN90101222A patent/CN1048659A/zh active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2355510A1 (fr) * | 1976-06-21 | 1978-01-20 | Toko Yakuhin Kogyo Kk | Procede de production de compositions pharmaceutiques renfermant un melange de solution aqueuse de polymere carboxyvinylique avec un compose basique |
US4525348A (en) * | 1983-12-19 | 1985-06-25 | Yoshitomi Pharmaceutical Industries, Ltd. | Pranoprofen gelled ointment |
Non-Patent Citations (1)
Title |
---|
STN INTERNATIONAL FILE SAVER (KARLSRUHE) & CHEMICAL ABSTRACTS, vol. 110, abstract no. 219086, Columbus, Ohio, US; & JP-A-63 130 540 (KOKAI TOKKYO KOHO) 18-11-1986 * |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GR1002351B (el) * | 1994-01-14 | 1996-05-29 | Bristol-Myers Squibb Company | Αντιφλεγμονωδεις συνθεσεις που περιεχουν πιροξικαμ (piroxicam). |
WO1998005360A2 (de) * | 1996-08-01 | 1998-02-12 | Basf Aktiengesellschaft | Verwendung von (meth)acrylsäure-copolymeren zur erhöhung der permeabilität der schleimhaut |
WO1998005360A3 (de) * | 1996-08-01 | 1998-05-07 | Basf Ag | Verwendung von (meth)acrylsäure-copolymeren zur erhöhung der permeabilität der schleimhaut |
US6555124B1 (en) | 1996-08-01 | 2003-04-29 | Basf Aktiengesellschaft | Use of (meth)acrylic acid copolymers to increase the permeability of mucous membranes |
US6312724B1 (en) | 1997-04-04 | 2001-11-06 | Isa Odidi | Sustained release pharmaceutical matrix tablet of pharmaceutically acceptable salts of diclofenac and process for preparation thereof |
US6509037B2 (en) | 1997-04-04 | 2003-01-21 | Isa Odidi | Sustained release pharmaceutical matrix tablet of pharmaceutically acceptable salts of diclofenac and process for preparation thereof |
EP2724716B1 (de) * | 2011-06-23 | 2017-11-22 | Prokrea Bcn, S.L. | Phosphodiestherase-inhibitoren zur transvaginaler verwendung in der behandlung der unfruchtbarkeit |
WO2014116770A1 (en) * | 2013-01-23 | 2014-07-31 | Arx, Llc | Production of unit dose constructs |
US9545376B2 (en) | 2013-01-23 | 2017-01-17 | Arx, Llc | Production of unit dose constructs |
US9662301B2 (en) | 2013-01-23 | 2017-05-30 | Arx, Llc | Production of unit dose constructs |
US9662297B2 (en) | 2013-01-23 | 2017-05-30 | Arx, Llc | Production of unit dose constructs |
US9814674B2 (en) | 2013-01-23 | 2017-11-14 | Arx, Llc | Production of unit dose constructs |
Also Published As
Publication number | Publication date |
---|---|
KR900013939A (ko) | 1990-10-22 |
AU5074890A (en) | 1990-09-13 |
CA2011682A1 (en) | 1990-09-08 |
JPH0347134A (ja) | 1991-02-28 |
DE69001372T2 (de) | 1993-09-09 |
NZ232797A (en) | 1991-07-26 |
EP0386688B1 (de) | 1993-04-21 |
IE900812L (en) | 1990-09-08 |
ES2055192T3 (es) | 1994-08-16 |
AU632794B2 (en) | 1993-01-14 |
DE69001372D1 (de) | 1993-05-27 |
PT93358A (pt) | 1990-11-07 |
CN1048659A (zh) | 1991-01-23 |
ATE88356T1 (de) | 1993-05-15 |
DK0386688T3 (da) | 1993-06-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6221399B1 (en) | Method of making controlled release particles of complexed polymers | |
CA1288344C (en) | Drug delivery system | |
Li et al. | Poly (vinyl alcohol) nanoparticles prepared by freezing–thawing process for protein/peptide drug delivery | |
Hora et al. | Release of human serum albumin from poly (lactide-co-glycolide) microspheres | |
EP0245820B1 (de) | Biologisch abbaubare Mikrokugeln als Träger für Makromoleküle | |
AU626031B2 (en) | New solid porous unitary form comprising micro-particles and/or nano-particles, and its preparation | |
KR100348585B1 (ko) | 다리페나신을함유하는약학제제 | |
KR960005141B1 (ko) | 서방성 제제 | |
KR100535319B1 (ko) | 약물방출속도가제어된의약조성물 | |
EP0274176B1 (de) | Formulierung für Kapsel oder Tablette mit verzögerter Freisetzung | |
BG64935B1 (bg) | Метод за леене под налягане на неутрални и съдържащи киселинни групи(мет)акрилат-кополимери | |
EP1392250A2 (de) | Acrylatpolymer enthaltende dosierungsform mit kontrollierter freigabe und verfahren zur herstellung | |
MXPA02007938A (es) | Sistema de suministro, composiciones y metodos, que utilizan un polimero biodegradable preformado. | |
EP2785330B1 (de) | Polymeres wirkstofffreisetzungsmaterial, verfahren zu seiner herstellung und verfahren zur verabreichung einer wirkstofffreisetzungszusammensetzung | |
JPH10502056A (ja) | 改質可能なでんぷんアセテート組成物およびその製造方法並びに使用方法 | |
EP0297978A2 (de) | Schwimmende therapeutische Zusammensetzungen mit anhaltender Wirkstofffreisetzung | |
EP0386688A1 (de) | Verfahren zur Herstellung von Hydrogelen und Xerogelen | |
KR100522239B1 (ko) | 아세트아미노펜을 함유하는 제어방출성의 경구용 제제 | |
US4491575A (en) | Compressed products with retarded release of active substance, a process for their preparation and a process for the long-term administration of medicaments | |
US4379038A (en) | Process for preparing a physiologically active substance controlled release composite composition | |
CN113426004B (zh) | 强亲水型微针基材与载药微针及其在治疗疾病中的应用 | |
US20230398143A1 (en) | Cis-platinum cross-linked protein hydrogel and preparation method thereof | |
JP5276448B2 (ja) | 昇華可能な持続放出デリバリーシステム及びその製造方法 | |
CN113786393A (zh) | 一种利伐沙班微球及其制备方法与应用 | |
JP2638604B2 (ja) | 徐放性製剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE |
|
17P | Request for examination filed |
Effective date: 19901221 |
|
17Q | First examination report despatched |
Effective date: 19911113 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 19930421 |
|
REF | Corresponds to: |
Ref document number: 88356 Country of ref document: AT Date of ref document: 19930515 Kind code of ref document: T |
|
ITF | It: translation for a ep patent filed |
Owner name: ING. C. GREGORJ S.P.A. |
|
REF | Corresponds to: |
Ref document number: 69001372 Country of ref document: DE Date of ref document: 19930527 |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: T3 |
|
ET | Fr: translation filed | ||
REG | Reference to a national code |
Ref country code: GR Ref legal event code: FG4A Free format text: 3008406 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Effective date: 19940306 Ref country code: DK Effective date: 19940306 Ref country code: AT Effective date: 19940306 |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: EBP |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19940307 Ref country code: ES Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19940307 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19940331 Ref country code: LI Effective date: 19940331 Ref country code: CH Effective date: 19940331 Ref country code: BE Effective date: 19940331 |
|
26N | No opposition filed | ||
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2055192 Country of ref document: ES Kind code of ref document: T3 |
|
BERE | Be: lapsed |
Owner name: HOECHST JAPAN LTD Effective date: 19940331 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Effective date: 19941001 |
|
GBPC | Gb: european patent ceased through non-payment of renewal fee |
Effective date: 19940306 |
|
NLV4 | Nl: lapsed or anulled due to non-payment of the annual fee | ||
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FR Effective date: 19941130 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DE Effective date: 19941201 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: ST |
|
EUG | Se: european patent has lapsed |
Ref document number: 90104245.7 Effective date: 19941010 |
|
REG | Reference to a national code |
Ref country code: GR Ref legal event code: MM2A Free format text: 3008406 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FD2A Effective date: 20030303 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES;WARNING: LAPSES OF ITALIAN PATENTS WITH EFFECTIVE DATE BEFORE 2007 MAY HAVE OCCURRED AT ANY TIME BEFORE 2007. THE CORRECT EFFECTIVE DATE MAY BE DIFFERENT FROM THE ONE RECORDED. Effective date: 20050306 |